The effect of cigarette smoking on postoperative morbidity following pancreaticoduodenectomy (PD) for cancer is unclear. We hypothesize that smoking is associated with higher morbidity following PD.A retrospective review of patients undergoing PD for cancer from 2010 to 2016 at a single institution was performed. Patients who had never smoked were compared to current or past-smokers with at least 1 pack-year history. Univariate and multivariable analyses were performed.Two hundred fifty-two patients met inclusion criteria. On univariate analysis, there was a significant difference between smokers and never-smokers in age at diagnosis (65.5 versus 68.6 y, P = 0.013) and fistula rate (28.5% versus 16.2%, P = 0.024). Male sex was significantly associated with fistula rate compared with female sex (15.5% versus 7.1%, P = 0.023). Comparing males and females separately, smoking correlated with higher fistula development only in the male cohort (22.5% versus 5.8%, P = 0.016 in men and 7.3% versus 9.1%, P = 1.00 in women). On multivariable analysis, current and past smoking was independently predictive of developing a fistula: odds ratio of 2.038 (P = 0.030). For current and past-smokers, male sex was an independent risk factor for developing a fistula: odds ratio 2.817 (P = 0.022). There were no other significant differences between groups in rates of postoperative complications.Smoking status is independently predictive of postoperative pancreatic fistula following PD for cancer. Among smokers, male sex is an independent risk factor for fistula. Further studies are needed to determine if smoking cessation before surgery decreases this risk, and if so, the optimal duration of cessation.